R-deprenyl and R-2-heptyl-N-methylpropargylamine prevent apoptosis in cerebellar granule neurons induced by cytosine arabinoside but not low extracellular potassium.
R-Deprenyl and R-2-heptyl-N-methylpropargylamine (R-2-HMP) are compounds that have been shown to reduce neuronal death in various in vitro and in vivo models involving apoptosis but do not always prevent apoptosis. In the present study we have examined the effects of these compounds and their S enantiomers on cytosine arabinoside (ara C)-induced apoptosis and low K+-induced apoptosis in cerebellar granule cells in primary culture. It was found that R-deprenyl and R-2-HMP could prevent ara C-induced apoptosis with an EC50 around 10(-9) M but could not prevent low K+-induced apoptosis. S-Deprenyl and S-2-HMP did not prevent apoptosis under any conditions but were found to antagonize the antiapoptotic actions of R-deprenyl and R-2-HMP. Using the fluorescent mitochondrial dye chloromethyltetramethylrhodamine methyl ester it was found that there was a loss of mitochondrial function in cerebellar granule cells exposed to ara C but not low K + medium. R-Deprenyl and R-2-HMP prevented the ara C-induced loss of mitochondrial function. It is concluded that R-deprenyl and R-2-HMP prevent apoptosis of cerebellar granule cells by a mechanism that is independent of monoamine oxidase inhibition and that they act on the same site to prevent specifically apoptosis involving a loss of mitochondrial membrane potential, possibly p53-dependent apoptosis.
Paterson
I A
IA
Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Zhang
D
D
Warrington
R C
RC
Boulton
A A
AA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000502:physiology; D003561:Cytarabine / Q000494:pharmacology*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012642:Selegiline / Q000494:pharmacology*
D011437:Propylamines; D003561:Cytarabine; C094098:N-2-hexyl-N-methylpropargylamine; D012642:Selegiline; D011188:Potassium